Providing multiple sclerosis patients with finished cannabis medicines

Spasticity is one of the relevant symptoms of multiple sclerosis (MS), which is associated with significant limitations in everyday life. Cannabis has been discussed as a possible option for insufficiently treatable spasticity for some time, but there were no approved preparations in Germany for a long time. This changed in the middle of last year when a finished cannabis-based medicinal product was launched onto the market in Germany for the first time. This meant that it was also “AMNOG-relevant” and, like all newly approved drugs since 2011, had to undergo an early benefit assessment in accordance with the requirements of the Medicines Market Reorganization Act (AMNOG). In the following, the importance and evidence of the new drug will be examined and the market penetration of the drug will be analyzed and whether therapy changes have taken place.

>> Multiple sclerosis (MS), which usually begins in young adulthood, is the most common chronic inflammatory disease of the central nervous system. In Germany, an estimated 120,000 to 140,000 people are affected by this disease. Over two thirds of them are women (Flachenecker et al. 2008). The attacks of the body's own defense cells on the myelin sheaths of the nerve cell processes lead to the loss of the insulating protective layers around the nerve fibers. Ultimately, this leads to disruptions in the transmission of stimuli or signals in the nerves, which results in different symptoms. Spasticity, i.e. persistent or temporary increases in muscle tone, which can sometimes be very painful, is one of the most common symptoms of the disease multiple sclerosis. The increased muscle tone is usually associated with significant reductions in mobility. According to data from the German MS registry, spasticity occurs in almost 60% of patients (Stuke et al. 2009). However, if the disease lasts less than 2 years, they are still relatively rare (17%); sensory problems or fatigue, for example, play a larger role here. However, as the disease progresses, spasticity becomes a serious problem; with a disease duration of over 15 years, 76% of patients are affected by spastic symptoms (Stuke et al. 2009). According to data from a North American registry, 17% suffer from severe to very severe spasticity associated with daily limitations (Rizzo et al. 2004). As part of the treatment of corresponding symptoms, muscle relaxants such as baclofen (“Lioresal” and others) or tizanidine (“Sirdalud” and others) are used, as well as the anticonvulsant gabapentin, which is not approved for this purpose (Henze et al. 2006). For severe adductor spasticity, botulinum toxin and, for severe spasticity, continuous intrathecal baclofen application via a pump are also mentioned as treatment options (DGN 2012). In addition, in non-drug procedures, intensive physiotherapy is a measure to normalize tone and increase mobility. Overall, the study situation is not really convincing, there is a lack of information on the benefits of antispastic treatment. Last but not least, the lack of a well-validated measurement method for spasticity can be blamed for this (Shakespeare et al. 2003).
Case reports were published over 20 years ago in which the authors described improvements in spasticity and ataxia (movement disorders) in MS patients after smoking marijuana (Meinck et al. 1989). In a British-American survey, 30 percent of respondents reported improvements in MS symptoms after cannabis consumption (Consroe et al. 1997). The active substances contained can dock onto receptors of the endocannabinoid system in the body and have a wide range of effects, particularly in the area of the central nervous system; muscle-relaxing effects have also been known for a long time (Williamson/Evans 2000). However, hopes were dampened in 2003 by a study published in the Lancet, in which there was no sufficient evidence of benefit for oral cannabinoid-containing preparations when measuring spasticity using the so-called Ashworth scale (Zajicek et al. 2003). Until mid-2011, there were no approved finished cannabis-based medicines on the market in this country. Until then, cannabis-containing preparations could only be purchased by affected patients for use as part of medically supervised and accompanied self-therapy in justified exceptional cases and after appropriate permission from the Federal Institute for Drugs and Medical Devices (BfArM) (BfArM 2009). In 2007, such an exemption was granted for the first time for a patient suffering from multiple sclerosis (amsel 2007).
Market launch of “Sativex”
The mouth spray “Sativex” for the treatment of spasticity in MS was launched on the German market in July 2011. This medication contains a plant extract mixture from the flowers and leaves of the hemp plant (Cannabis sativa) and is sprayed onto the inside of the cheeks as the active substances can be easily absorbed through the oral mucosa. The active ingredient mixture, also known internationally as Nabiximols, contains standardized amounts of the ingredients tetrahydrocannabinol (THC) and cannabidiol. “Sativex” is the first and currently only finished cannabis-based medicinal product in Germany. The indication is limited to patients who do not respond to other medications to correct spasticity and who demonstrate clinically significant symptom improvement during an initial trial of therapy with the new medication. The mouth spray is intended as an additional treatment to the anti-spastic medication already used by the patient. In order for it to be marketed at all, an amendment to the Narcotics Act was required, which came into force on May 18, 2011. The position “Cannabis - only in preparations that are approved as finished medicinal products” was added to Annex III, which lists the marketable and prescription-ready narcotics. “Sativex” is also currently the only anesthetic that requires refrigeration. This presents pharmacies and wholesalers with particular challenges in terms of storage. Some wholesalers do not deliver or do not deliver “Sativex” at all because they shy away from implementing such requirements (“apotheke adhoc”, 2011).
Study situation for finished cannabis medicinal products
“Sativex” was tested against placebo in three double-blind randomized controlled trials (RCT) with a total of 767 MS patients who showed treatment-resistant spasticity (Collin et al. 2007;Collin et al. 2010;Novotna et al. 2011). In all three studies, the average number of sprays used per day was between 8 and 9. Patients were able to continue with previous treatment, including anti-spasticity therapy. The primary endpoint was changes in symptom severity, measured using a patient-completed numerical rating scale ranging from 0 (subjective no spasticity or stiffness) to 10 (maximum spasticity). This scale has not been used before. In the first two studies (Collin et al. 2007;Collin et al. 2010), the manufacturer failed to apply for approval in Great Britain: the six-week study showed more responders and improvements in symptom scores than in the placebo study arm (Collin et al . 2007), but this could not be confirmed in the 15-week study (Collin et al. 2010).
In the recent clinical study by Novotna et al. (2011), a so-called “enrichment” procedure was now used: First, 572 patients were analyzed in a four-week, single-blind study phase and only those who responded to the “Sativex” treatment with at least a 20 percent improvement in symptoms (48%, n =272), were randomly assigned to the double-blind treatment phase. Ultimately, data from 241 MS patients (42%) were collected in the following 12-week study phase. In the “Sativex” study arm there were slight, statistically significant improvements in the symptom score (-0.04 points) compared to slight deteriorations with placebo therapy (+0.81 points) (95% confidence interval -1.29- -0 ,40). The responder analysis showed that those affected responded with at least a 30 percent improvement compared to the original baseline values under therapy with “Sativex” 74% (placebo: 51%). Overall, however, the symptom improvements can be classified as minor. No significant difference was found in a standardized measurement using the commonly used Ashworth score. It is possible that this was not chosen as the primary endpoint in the above-mentioned approval studies, as an older study (Zajicek et al. 2003) showed no evidence of a relevant benefit in the form of score improvements from cannabis in MS spasticity (at 2011) .
In the regulatory studies cited, at least one side effect occurred in over 80% of patients treated with the cannabis oral spray. In total, data for 1,500 patients are available from the entire clinical study program. Very often, i.e. at least 1 in 10 patients, dizziness and fatigue occur while taking the medication. Compared to smoking the cannabis herb (marijuana), use as a mouth spray is said to be associated with a lower absorption of the active substance tetrahydrocannabinol (THC) across the blood-brain barrier into the brain, associated with correspondingly fewer typical psychological side effects (Karschner et al. 2011). Nevertheless, even when the spray is used oromucosally (via the oral mucosa), psychological side effects such as euphoria, depression and memory disorders often occur, i.e. in less than 1 in 10, but in at least 1 in 100 patients, according to the specialist information (Almirall 2011). Due to various undesirable effects such as vision and balance problems, the risk of falling is also increased.
“Sativex” and the early benefit assessment
According to the requirements of the Medicines Market Reorganization Act (AMNOG), which came into force in 2011, all drugs with new active ingredients must undergo an early benefit assessment after approval, which is then later used as the basis for price negotiations between the National Association of Statutory Health Insurance Funds and the manufacturer. This also happened with the drug “Sativex”. The Institute for Quality and Efficiency in Health Care (IQWiG), which was responsible for the benefit assessment, was unable to find sufficient evidence for an additional benefit (IQWiG 2012). According to the G-BA, in order to achieve an optimized comparative therapy, at least two previous therapy attempts should have been carried out, in each of which different muscle-relaxing drugs (spasmolytics), at least one of which had the active ingredients baclofen or tizanidine, were used in an optimized manner. However, in IQWiG's opinion, there was insufficient data for these defined criteria, which was crucial for the evaluation.
In its evaluation dossier, the manufacturer Almirall mentioned the continuation of pre-medication as a comparator therapy and justified this by saying that it can be assumed that the spasticity treatment has been optimized in patients undergoing longer treatment. The IQWiG did not follow this view and saw this as a deviation from the appropriate comparative therapy, which, as expected, led to a variety of contradictions from the pharmaceutical industry. The Federal Association of the Pharmaceutical Industry called the method of evaluation a “devastating result” because continuous optimization of the comparative therapy would reduce the reality of treatment to absurdity (BPI 2012).
The question is when one can say that the response to previous spasticity treatment was not sufficient and how these response rates should be operationalized. In this context, it is welcome that the G-BA wants to justify the comparative therapy in detail in writing in the future, so that there would also be more clarity for the pharmaceutical manufacturers (aerzteblatt.de 2012). Ultimately, the G-BA deviated from the IQWiG assessment in its decision on the additional benefit of “Sativex”, which came into force on June 21, 2012, and recognized the comparison therapy chosen by the manufacturer for the assessment. The joint self-administration saw no deviation from essential requirements and, unlike IQWiG, assumes that patients with optimized anti-spasticity therapy were integrated into the relevant studies (G-BA 2012). Although the G-BA noted uncertainties in the data, it did not consider the study from the manufacturer's dossier to be unsuitable for a benefit assessment of the Cannabis sativa extract. Ultimately, the G-BA recognized evidence of minor additional benefit for the new drug compared to optimized standard therapy with baclofen or tizanidine or other active ingredients that are approved for the treatment of spasticity in underlying neurological diseases. However, the G-BA also writes in its justification that it cannot be deduced from the available data how large the proportion of patients is who have already experienced optimization of standard therapy before the start of the study. It therefore remains unclear for how many patients further optimization would have been possible during the course of the study. Ultimately, the extent of additional benefit described by the G-BA only applies to the cohort of responders, i.e. to those patients who responded positively to Cannabis sativa in an initial therapy trial, but not to the entire population. The period of validity of the decision was limited to three years because, in the G-BA's opinion, the data from the dossier cannot be used to predict with sufficient certainty how many cases of treatment a therapy will be successful (G-BA 2012).
Supply with “Sativex” in the BARMER GEK
In the following, prescription data from a health insurance company will be used to examine which patients were placed on the new finished medicinal product containing cannabis extract and what the anti-spastic pre-therapy looked like. This can provide information about the extent to which the approval requirements are taken into account in everyday care.

methodology
For the historical analysis, prescription data from insured persons who were insured with BARMER GEK for at least one day in each quarter in 2010 and 2011 were evaluated. The BARMER GEK is the largest statutory health insurance company in terms of the number of members (over 9 million insured people). The restriction to consistently insured persons is intended to ensure that there are no changes in results due to the entry or exit of insured persons over the course of the year. For example, the process also takes into account data from insured persons who died during the last quarter. The selected insured persons were analyzed with regard to their medications, which were identified using the Anatomical-Therapeutic-Chemical (ATC) classification system. For the longitudinal study of “Sativex” pretherapy, all muscle relaxants (ATC code M03) and gabapentin, which is used “off-label” for spasticity (DGN 2012), were taken into account.
Results
404 patients were identified who had been insured since the first quarter of 2010 and were prescribed the finished cannabis drug “Sativex” at least once during 2011. Table 1 shows the basic data of these patients, over two thirds (69.6%) of whom are female. On average they were 52.2 years old, with only adults receiving a corresponding prescription. Most commonly, physicians coded the diagnosis “MS, unspecified” (58.1%). The most frequently diagnosed subtype was relapsing-remitting MS (14.4%), closely followed by the secondary-chronic form (12.9%). Table 2 lists the prescribing specialist groups according to the number of prescriptions. Neurologists (or psychiatrists) were responsible for around two thirds (66.4%) of the 688 “Sativex” prescriptions, followed by general practitioners/internists (16%). In July 2011, the month of the market launch, 72 packs were prescribed, after which the volume increased slightly each month until the maximum was reached in November with 156 packs prescribed. In December 2011 there was a slight decrease to 120 packs (Fig. 1).
Fig. 2 shows which immunomodulating and suppressing active ingredients were used in the drug treatment of MS for relapses and disease progression among insured persons with a “Sativex” prescription. With the exception of natalizumab (2010: 3.5%; 2011: 4.2%), the prescription prevalence was higher in 2010, the previous year based on the year of “Sativex” market launch. The highest proportion of patients with corresponding prescriptions was recorded for glucocorticoids, i.e. medications for treating flare-ups of the disease. In both years, the parenteral dosage forms were used more frequently (28.7% and 23.0%) than the oral ones (18.6% and 16.1%). For the immunomodulating beta-interferons and glatiramer, the prescription prevalence was between 5 and 10%.
Figure 3 shows what the muscle relaxant or spasmolytic drug therapy looked like in patients who were later prescribed “Sativex”. For 17.3% of the included patients, there was no prescription for any other muscle-relaxing (spasmolytic) active ingredient in the period up to the first prescription of the cannabis mouth spray. On the other hand, a proportion of 12.1% was previously prescribed three and a proportion of 6.5% even four to seven different antispasmodic agents. Since the initial “Sativex” prescription, 57% also received prescriptions of other antispasmodics until the end of 2011. Accordingly, 43% (n=174) were only prescribed “Sativex” from this point on, with 110 of these patients being prescribed until December 31st. there was only a one-time prescription for the new medication.
discussion of the results
With the first finished cannabis-based medicinal product in 2011, the range of anti-spasticity treatment for MS sufferers was expanded. That of around 30,000 insured people who have an MS diagnosis code in the routine data of the BARMER GEK (Windt 2012), over one percent were prescribed this preparation at least once in the first six months after its market launch, and this was a second-line medication for symptoms , which usually only become relevant at an advanced stage, can definitely be described as a success for the information provided by the pharmaceutical manufacturer. Future analyzes could show whether market penetration can be further expanded or whether the negative assessment of IQWiG from April 2, 2012 will influence the prescription figures in the meantime. In general, multiple sclerosis is an indication area in which medications are used outside the approved range (“off label”) or are sometimes even recommended, due to, among other things, a lack of or exhausted therapy options. Examples include modafinil for the treatment of MS fatigue (Frost et al. 2011), gabapentin as a muscle relaxant (Bittner et al. 2011) or intravenous immunoglobulins to influence the course of the disease (Cursiefen/Mäurer 2008). This study also showed evidence of non-compliant use of “Sativex”, even though it is approved for the indication multiple sclerosis: 17% of patients with the corresponding prescription had not received any medication for a period of at least one and a half years before the first use antispastic therapy, although according to the approval “Sativex” should only be used if other anti-spastic drug therapies fail. There is no change in therapy here, but rather an immediate readjustment to this cannabis mouth spray. However, in a similar proportion of patients (18.6%), at least three additional antispasmodic agents were prescribed in the period from January 1, 2010. In this context, one could assume that MS spasticity is difficult to control, but this cannot be verified based on the available data, which do not contain any clinical information. At least at first glance, a therapeutic attempt with cannabis mouth spray seems obvious. The question of whether the new drug will be used as an add-on drug to existing anti-spasticity therapy or as a monotherapeutic (“off label”) in accordance with the approval can be answered due to the short analysis time window since “Sativex” was launched on the market cannot be answered with sufficient certainty with the available data. What is welcome, however, is the fact that around two thirds of the doctors prescribing “Sativex” were neurologists. According to the product information, treatment should be started and monitored by a doctor with expertise in the treatment of this patient group (Almirall 2011). It is not surprising that fewer younger people and no patients under the age of 18 receive the drug, as “Sativex” is not recommended for children and adolescents according to the product information (Almirall 2011). However, this observation is also due to the fact that in this patient group, spasticity does not yet play a major role in MS symptoms due to the short duration of the disease (Stuke et al. 2009). When evaluating the diagnoses of patients with “Sativex” prescription, it was noticeable that the majority of doctors coded non-specifically (“MS, unspecified”). This phenomenon can also be observed in other diseases (Grobe et al. 2008). However, it turns out that the secondary-chronic form of the disease is proportionally close behind the relapsing-remitting form of MS. Normally, relapsing-remitting MS is clearly the most common subtype (Weinshenker et al. 1989). In the area of spasmolytic treatment, the secondary-progressive form, which manifests itself after a long period of illness of 10 to 15 years, is a relevant indication area, as spasticity plays a dominant symptom role here (Stuke et al. 2009).
A major advantage of the studies presented here is that a correspondingly large group of MS patients could be examined using data from the largest German health insurance company. Since MS is not a very common disease with around 120,000 to 140,000 patients in Germany (Flachenecker et al. 2008) and severe spasticity only occurs in a certain percentage of these patients, despite the large collective as well as the insured population of the BARMER GEK, just over Out of 9 million insured people, only a relatively small number of insured people with the “Sativex” prescription were identified. In comparison to all MS patients from the BARMER GEK insured population (evaluation of data from 2010) (Windt 2012), the proportion of male patients with “Sativex” prescription in the present study was lower (70% vs. 77%). Patients were also slightly older (52.2 years vs. 50.4 years).
Despite a large group of insured persons, there are limitations with regard to the transferability of the results. For example, other health insurance companies could produce different results, favored by structural differences between the collectives that persist even after adjustments (Hoffmann/Icks 2012). In general, it should be noted that routine data is originally collected for administrative purposes (billing reasons, etc.), but not for research purposes. Diagnostic data could only be taken into account for the year 2010, as no more recent data was available at the time of the examination. In addition, only outpatient prescription data were recorded; we had no information on drug applications in hospitals or private prescriptions.
Conclusion
Spasticity is one of the relevant symptoms of multiple sclerosis, which is associated with significant limitations in everyday life. With “Sativex”, the first cannabis-based finished medicinal product, the range of therapies in this area has been expanded. Even if the Federal Joint Committee recognized the appropriate comparator therapy from the manufacturer's dossier in contrast to the IQWiG as part of the benefit assessment and found an indication of a minor additional benefit, questions remain unanswered.
Further studies are required so that a “hint” of minor added benefit can eventually become “proof”. Accordingly, the validity of the decision is initially limited to three years. Due to inconsistencies in the studies and pronounced side effects, this mouth spray with cannabis extracts should only be used in patients who do not respond adequately to optimized therapy with more proven medications and who show a positive response to the new preparation until further information is available. The evaluations of the prescribing practice showed that in some cases there was no pretreatment with medication and therefore no optimization of anti-spasticity therapy. Further routine data analyzes could show, in the sense of policy follow-up research, whether and how the market penetration of new drugs such as “Sativex” changes under the influence of positive or negative reviews of the additional benefit. Studies from the field of health services research could be particularly helpful if, after an early evaluation of new drugs according to AMNOG, which is usually viewed as a preliminary evaluation, a late evaluation should be carried out (Glaeske 2012). <<